Monocyte apoptosis has emerged as a pivotal mechanism for controlling the outcome of inflammatory responses. Inflammatory mediators such as LPS, IL-1beta, and TNFalpha have been shown to prolong the life-span of human peripheral blood monocytes, and their depletion leads to apoptosis of the cells. However, the activation-dependent survival of monocytes is abolished by IL-4, an antiinflammatory cytokine or by anti-Fas antibody, suggesting that apoptosis is a fundamental mechanism for removing activated monocytes when inflammation is no longer necessary. To define the intracellular pathway leading to monocyte death, we have characterized monocyte apoptosis induced by IL-4 or anti-Fas. Activation of monocytes with cytokines or bacterial product differentially alters their susceptibility to anti-Fas and IL-4, suggesting two different apoptotic pathways. Furthermore, N-acetylcysteine (NAC), a scavenger of peroxides, inhibits apoptosis induced by anti-Fas which increases cellular levels of peroxides, but not by IL-4. In contrast, PMA, a stimulator of PKC, inhibits death mediated by IL-4, but not by anti-Fas. The role of PKC to protect monocytes from death is further supported by a PKC-specific inhibitor, calphostin C which induces apoptosis in activated monocytes. The sum of these data clearly indicates two distinct apoptotic pathways in monocytes; one involving the formation of peroxide and the other inhibited by PKC. Further unraveling of these unique pathways and their regulatory mechanism is expected to provide important information to determine potential therapeutic targets of inflammatory diseases. In this regard, experiments have been initiated to explore the role of apoptosis in chronic destructive disease and how it is regulated by immunomodulators. In additional studies to define signalling pathways for activation, rather than death, we have shown that monocyte-matrix interactions trigger jak- stat kinase signalling and augmentation of IFNgamma gene induction. Inhibition of these pathways by synthetic peptide antagonists downregulates monocyte signalling and inflammatory sequelae.